Oxidation of the enamine of alpha,beta-unsaturated ketones



United States Patent 3,514,475 OXIDATION OF THE ENAMINE OF0:,fi-UNSATURATED KETONES Sudarshan K. Malhotra, Northboro, Mass.,assignor to The Dow Chemical Company, Midland, Mich., a corporation ofDelaware No Drawing. Filed July 29, 1968, Ser. No. 748,208 Int. Cl. C07c167/34 U.S. Cl. 260-397.2 9 Claims ABSTRACT OF THE DISCLOSURE A processfor producing, a,6-diketones which comprises reacting the enamine of anu,6-ethylenically unsaturated ketone with molecular oxygen to produce anoxidized enamine intermediate which is thereafter hydrolyzed to thecorresponding compound having keto groups at the a and 6 positions.

BACKGROUND OF THE INVENTION Enamines and enolate anions derived froma,B-unsaturated ketones undergo electrophylic attack at the a-carbonatom. The auto-oxidation of the enolate anions of these ketones alsoinvolves attack at the a-carbon atom leading predominantly to thea-ketone products having a hydroxy substituent at the 6 position. Theenamines on the other hand, unlike the enolate compounds, undergoauto-oxidation giving mainly the 'y-ketone (oxidized enamine)intermediates which upon hydrolysis in acid medium yield thecorresponding unsaturated compounds having keto groups at the a and 6positions.

The oxidation reaction of the present invention difiers from the artprocesses in its specificity and in its use of less severe reactionconditions. These differences enable the process of the presentinvention to be employed in the use of the complex molecules such assteroids where side reactions in other portions of the molecule veryoften occur using known oxidation procedures.

GENERAL DESCRIPTION OF THE INVENTION The present invention is directedto a process for the preparation of a,6-diketones from an enamine of antag/3- ethylenically unsaturated ketone possessing a methylene group atthe 6-position, said process comprising oxidizing the enamine of theonfl-ethylenically unsaturated ketone with molecular oxygen to producean oxidized enamine intermediate which is thereafter hydrolyzed to thecorresponding compormd having keto groups in the a and 6 positions. Inthe present specification and claims, for convenience, the final productpossessing keto groups in the oz and 6 positions will be referred to asan a,5-dione.

In the present specification and claims, the term enamine refers to thereaction products of a secondary amine and an a ti-unsaturated ketoneand generally can be said to be represented by the formula l I wherein Rrepresents a lower alkyl moiety having from 1 to 4 carbon atoms,inclusive, and the R groups can be linked by means of a methylene moietyor a hetero atom such as O or N to produce a heterocyclic ring of 5 or 6members.

The enamine of the present invention is prepared by reacting together asecondary amine such as pyrrolidine, morpholine, piperidine, or adialkyl amine having from 2 to 4 carbon atoms per alkyl group,inclusive, and an o e-unsaturated ketone having a methylene group in the'y-position. Representative a,;3-unsaturated ketones are cholestenone,testosterone, 19-nortestosterone, progesterone, 1O-methyPA -2-octalone,erogesterone, androst- A -en-3,17-dione, androst-A-diene-l7-l3-ol-3-one, pregna A -diene-5-,8-hydroxy-2O-one, A-2-octalone and any other similar erg-unsaturated ketones. However,unsaturated ketones bearing bulky substituents are not desirable as themolecule may be sterically hindered, preventing the formation of theenamine or the subsequent formation of the enamine or the subsequentformation of the corresponding a,B-dione.

The oxidation of the enamine is elfected by molecular oxygen. Any gascontaining molecular oxygen may be utilized as the oxygen source and ina convenient procedure air is employed. The oxidation reaction takesplace readily at temperatures of from 5 to C. and most conveniently atroom temperature. The reaction mixture is maintained at the reactiontemperature for from about 1 to 48 hours. However, the reaction periodcan be cut by as much as 20 to 30 times by the addition of a catalyticamount of a metal salt catalyst to the reaction mixture. Representativemetal salt catalysts include ferric chloride, ferric nitrate, ferricacetate, cupric chloride, cupric nitrate, cupric acetate, stannicchloride, mercuric chloride and lead chloride. The reaction scheme isassumed to be as follows:

5 cond 0=& 5 amin e R\ I h d 1 r0 SIS /N\ /(.L\ y Oz O=(l1\ /C R \C \CC/ \C l l l H The oxidation of the enamine is carried out in an inertorganic solvent as reaction medium. Representative inert organicsolvents include diglyme, monoglyme, methanol, hexane, benzene or otherinert organic liquids in which the enamine is soluble so as to produce ahomogeneous reaction mixture. When the present invention is carried oututilizing a metal salt catalyst, it may be necessary to employ aco-solvent such as hexamethylphosphoramide, methanol, ethanol,t-butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide orthe like to produce a homogeneous reaction mixture. The amount ofcosolvent to be employed will vary depending upon the solvent utilizedand upon the amount of catalyst employed.

The enamine is dissolved in the inert organic solvent in an amountsufiicient to provide a reaction mixture containing from about 0.1 toabout 10 percent by weight of the enamine with respect to the weight ofthe total reaction mixture. The use of a reaction mixture containinggreater than 10 percent enamine is not desirable as such an increase inenamine concentration often results in undesirable side reactions. Inthose cases where a metal salt catalyst is employed, the metal salt ormixture of metal salts is added to the reaction mixture in an amountsufficient to provide from about .01 to 40 percent of a molar equivalentwith respect to the amount of enamine employed.

In carrying out the process of the present invention, the enamine isdissolved in the organic reaction medium to produce a homogeneousreaction mixture. Following the production of the homogeneous reactionmixture, the oxidation of the enamine is effected by the addition ofmolecular oxygen to the reaction mixture. The molecular the addition ofthe molecular oxygen is effected by bubbling a gas such as air throughthe reaction mixture. During the addition of the molecular oxygen, thetemperature of the reaction mixture is maintained within the reactiontemperature range. As a result of the oxidation of the enamine, anoxidized enamine intermediate is produced in the reaction mixture. Thisoxidized enamine is hydrolyzed to the corresponding a,6-dione byacidifying the reaction mixture. The reaction mixture is made acidic bythe addition thereto of an acid such as dilute acetic, oxalic, sulfuricor hydrochloric acid. Following the acid hydrolysis of the oxidizedenamine to'the corresponding u-6-dione, the product is isolated from thereaction mixture by known procedures. In a representative procedure, theacidic reaction mixture is extracted with an organic solvent in whichthe a,5-dione is soluble such as ether, ethyl acetate, benzene, ormethylene chloride and the resulting organic extract is neutralized witha weak base such as dilute aqueous sodium bicarbonate. The neutralizedorganic layer is then dried and concentrated in vacuo to remove the lowboiling constituents and obtain the corresponding a,6-dione product as aresidue.

In an alternate procedure, the enamine starting material of the presentinvention is prepared by reacting together a secondary amine and an oe-unsaturated ketone having a 'y-methylene group. The enamine thusproduced is then oxidized in situ to produce the oxidized enamineintermediate which is hydrolyzed to the a,5-dione product. In thisalternate embodiment, the secondary amine and cap-unsaturated ketone aredispersed in an inert organic solvent as previously described and theresulting reaction mixture maintained at a temperature of from 5 to 85C. for from about 1 to about 48 hours. The reaction consumes thesecondary amine and u,fl-unsaturated ketone in equimolar proportions andthe use of such proportions is preferred. While the use of substantiallyequimolar proportions is preferred, large excesses of c p-unsaturatedketones with respect to the secondary amine can be employed withoutadversely affecting the process; however, large excesses of thesecondary amine are not recommended as they may cause undesired sidereactions during the in situ oxidation of the enamine. The in situoxidation of the enamine is eifected by the addition of molecular oxygento the reaction mixture as previously described and the desired productis separated from the reaction mixture by known procedures.

SPECIFIC EMBODIMENTS The following examples are merely illustrative andare not deemed to be limiting.

Example 1.Oxidation of the pyrrolidine enamine of A -andro stem-317-dione The pyrrolidine enamine was prepared by dissolving pyrrolidine(1 ml.) and A -androsten 3,17 dione (0.7 gram) in 20 milliliters ofmethanol and heating the resulting reaction mixture on the steam bathfor a feW minutes. During the heating procedure, the crystallinepyrrolidine enamine of A -androsten-3,17-dione precipitated from thereaction mixture, was isolated by filtration and dried. The driedpyrrolidine enamine of A -androsten- 3,17-dione 750 mg.) was found tomelt at 207 to 208 C. A portion of this pyrrolidine enamine wasdissolved in 200 milliliters of benzene (350 mg.) and a solution offerric chloride (50 mg.) in milliliters of hexamethylphosphoramide addedthereto. The reaction mixture thus produced was maintained at roomtemperature and air bubbled through the reaction mixture at a rate of100 milliliters per minute for 1 hour. Following the addition of the airto the reaction mixture, 25 milliliters of 1 N HCl was added to thereaction mixture and the mixture stirred for minutes whereupon theacidified reaction mixture was extracted with ether and the etherextract washed with sodium carbonate, dried and stripped in vacuo togive the A -androsten-3,6,17-trione product as a solid residue. Thissolid product was recrystallized from methanol and the recrystallizedproduct found to melt at from 215 to 225 C.

Example 2.-Oxidation of the pyrrolidine enamine of progesterone Thepyrrolidine enamine of progesterone (370 mg.) and ferric chloride mg. in10 milliliters of hexamethylphosphoramide) were dissolved in 200milliliters of benzene. Air was bubbled through the reaction mixturethus prepared, the reaction mixture acidified and the product isolatedall as described in Example 1. The 6-keto-progesterone product wasrecrystallized from an acetonehexane mixture and found to melt at 188 to190 C.

Example 3.Oxidation of the pyrrolidine enamine of 19-nor-testosteronePyrrolidine enamine of 19-nor-testosterone (500 mg.) and ferric chloride(50 mg.) were dissolved in a mixture of 200 milliliters of benzene and 5milliliters of methanol. Air was passed through the resultant reactionmixture for 15 minutes at room temperature. Following the addition ofair, the reaction was acidified by the addition of 10 percent HCl. Theacidified reaction mixture was then neutralized with sodium carbonate,extracted with ether and the ether extract was washed with water anddried over anhydrous magnesium sulfate. The dried ether ex tract wasthen stripped in vacuo to give a semi-crystalline product. Thissemi-crystalline product showed infrared absorption bands at 1720 cm."to 1670 cm.- and a maximum absorption of ultra-violet at 250millimicrons. The infrared and ultraviolet spectrum analysis confirmedthe identity of the product as being l7-fi-hydroxy-A -estren-3-one.

Example 4 In similar procedures, the following, a,6-diones are prepared:

4-cholestene-3,6-dione (M.P. 123-l24 C.) by oxidizing with air thepyrrolidine enamine of 4-cholestene- 3-one (M.P. 184-186 C.) at 25 C.for 1 hour in a henzene-hexamethylphosphoramide reaction medium withferric chloride as catalyst.

4-cholestene-3,6-dione (M.P. 123 l24 C.) by oxidizing the pyrrolidineenamine of 4-chloestene-3-one (M.P. l84l86 C.) with air at roomtemperature for 1 hour in a benzene-hexamethylphosphoramide reactionmedium with cupric chloride as the catalyst.

10-methyl-A -octalin-2,6-dione (M.P. -72 C.) by oxidizing with air themorpholine enamine of 10- methyl-A -octalone-2 at the reflux temperaturefor 1 hour in benzenedimethylsulfoxide reaction medium with cupricchloride as a catalyst.

8-methyl-5,6,7,8-tetrahydro-indane-3,S-dione (mol. wt. 188.1) byoxidizing with air the pyrrolidine enamine of8-methyl-5,6,7,8-tetrahydro-indanone-5 at room temperature for 1 hour ina benzene-hexamethylphosphoramide reaction medium as reaction mediumwith ferric chloride as catalyst.

4-cholestene-3,6-dione (M.P. 123124 C.) by oxidizing with air thediethyl amine enamine of 4-cholestene- 3-one at room temperature for 1hour in benzene-dimethyl sulfoxide reaction medium with ferric chlorideas catalyst.

4-cholestene-3,6-dione (M.P. 123 124 C.) by oxidizing with air thepyrrolidone enamine of 4-cholestene- 3-one at 15 C. for 2 hours inmonoglyme-benzene mixture as reaction medium with ferric chloride ascatalyst.

Example 5 l0-methyl-A -octalin-2,8-dione (M.P. 70-72 C.) was prepared byoxidizing the pyrrolidine enamine of 10 methyl-A -octalone-2 (B.P.149-150 C./1 mm. of Hg). The oxidation was carried out at roomtemperature for 16 hours. Following the oxidation procedure, the enamineintermediate was hydrolyzed with 50 percent acetic acid and the finalproduct separated as previously described.

In an alternate procedure, the pyrrolidine enamine of -methyl-A-octalone-2 was oxidized in the presence of a catalytic amount of ferricchloride. The oxidation procedure was carried out at room temperaturefor 1 hour. Following the oxidation period, the enamine intermediate washydrolyzed with 50 percent acetic acid and the desired product separatedas previously described. Yield 75 percent.

The enamine starting materials employed in the present invention areprepared in accordance with known methods. A representative methodincludes reacting together the secondary amine such as pyrrolidine,morpholine, dimethyl amine, diethyl amine, piperidine and dibutyl amineand the u,fi-unsaturated ketone in the presence of an inert organicsolvent as a reaction medium. The reaction is readily carried out at atemperature of 25 to 100 C. and most conveniently at the refluxtemperature of the reaction mixture. The enamine generally precipitatesfrom the reaction mixture and can be separated therefrom by filtration.In those cases where the enamine does not precipitate from the reactionmixture it can be isolated therefrom by removing the reaction medium andother low boiling constituents to leave the desired enamine product as aresidue.

I claim:

1. The method for preparing an tam-dione containing the moietycorresponding to the formula comprising oxidizing With molecular oxygenthe enamine of an afi-ethylenically unsaturated ketone having amethylene group in the 6-position to produce an oxidized enamineintermediate which is thereafter hydrolyzed with acid to saida,5-di0118; said enamine starting material containing the moietycorresponding to the formula comprising reacting together, in an inertorganic solvent as reaction medium, (a) a secondary amine selected fromthe group consisting of diloweralkyl amines and heterocyclic amineshaving 5 or 6 members, and (b) an 04,,8- ethylenically unsaturatedketone having a methylene group in the 'y-position; said reactionproducing an enamine containing the moiety corresponding to the formulaoxidizing said enamine with molecular oxygen and there after acidifyingthe reaction mixture to produce the u,6- dione product.

6. The method of claim 5 wherein the metal salt catalyst is present inan amount of from 0.1 to 40 percent of a molar equivalent with respectto the amount of enamine employed.

7. The method of claim 5 wherein the reaction is carried out at atemperature of from 5 to C.

8. The method of claim 5 wherein the oxidation is carried out in thepresence of a metal salt catalyst.

9. The method of claim 5 wherein the secondary amine is pyrrolidine,morpholine, piperidine, dimethyl amine or diethyl amine and thea,fi-ethy1enically unsaturated ketone is an a,,B-ethylenicallyunsaturated mono-keto-steroid.

No references cited.

ELBERT L. ROBERT, Primary Examiner US. Cl. X.R.

